Multi-Drug-Resistant (MDR) bacteria have presented a major public health concern for several years now. An estimated 700,000 deaths per year are attributed to MDR pathogens worldwide1. Additionally, several prediction models have been published in the literature, indicating that this number could grow exponentially in the next few decades2. While progress on the matter had not been initially observed, things are slowly taking a more positive turn. There have been coordinated efforts undertaken by several authorities, with the participation of various regulatory as well as scientific disciplines throughout the world. While there is still a long way ahead of us, this article presents an overview of the scientific evidence that may put us in a position to take a more positive glimpse into the future.
A new molecule with the potential to combat MDR bacteria was presented In an article3 published by Nature on November 20, 2019. Darobactin, a peptide derived from the intestinal bacterial flora of a parasitic worm, was demonstrated to exert bactericidal activity against gram-negative resistant bacteria, such as E Coli. The investigators demonstrated a novel mechanism of action for this effect, which was mediated by the binding of darobactin to BamA proteins located in the external membranes of gram-negative bacteria. This ultimately resulted in bacterial cell wall lysis. The authors stated that this cite of action presents an attractive target since darobactin did not have to penetrate the bacterial membrane to exert its effect.
While this report presented data of potentially high scientific value, this evidence came from an experimental model on mice and is still a long way before it is of any importance to clinical practice. In recent years there has been a rather large body of similar evidence identifying new potential targets for antibacterial activity. One such example would be a class of small molecules, termed nusbiarylins, which disrupt the interaction between proteins involved in ribosomal RNA synthesis. These compounds were active against strains of MRSA, with significantly lower MICs than standard agents, such as oxacillin, gentamycin and vancomycin4. Interestingly enough, nusbiarylins did not seem to cause toxicity to cultured human lung and skin cells.
Another example would be two molecules that were developed from a newly identified streptococcal toxin. Investigators were able to isolate these two compounds, which subsequently demonstrated activity against both gram-positive and negative bacteria5. These novel agents, termed peptidomimetics, were the two of twenty originally formulated compounds that demonstrated superior activity. Of particular interest in this experiment was that resistance to these agents was not developed, even when favorable conditions for such an event were created by the investigators for a time frame of fifteen days.
Finally, the most scientifically intriguing source of potential antibacterial agents to date is that of bacteriophages6,7,8. The term refers to a class of viruses that exhibit a selective predatory effect on bacteria while maintaining a symbiotic relationship with most living host-organisms. These viruses use the bacterial host’s structures to replicate, while destroying the cell membrane, ultimately causing bacterial cell lysis. Several studies have reported on the potential benefits of bacteriophages since they present an area of particular interest in the field of biotechnology.
This information is of particular interest in light of one of the most widely addressed public health issues worldwide. The development of MDR bacteria has been in the centre of actions taken by several authorities, including the World Health Organization, the Centers for Disease Control in the US, and the European Union counterpart. Antimicrobial stewardships, as well as public awareness campaigns, have been implemented for many years, with demonstrated positive outcomes. Overall, our attempts to restrict antibiotic use have lead to the implementation of several effective strategies.
However, there had been growing concerns regarding the lack of the development of novel antibacterial agents. In fact, we are still using several antibiotics that were developed 40-50 years ago as first-line agents for certain infections. That has certainly given bacteria enough time to evolve through natural selection and develop mechanisms of resistance. While the development of such agents presents with unique pharmacological as well as economic challenges, things seem to be on the verge of a shift in the right direction.
According to PEW9, there are 42 different agents that are currently being investigated as potential new antibiotics. The main focus area for these agents is their possible activity against MDR bacteria. Future clinical trials will also determine their pharmacokinetic and toxicity profiles, as well as the potential for the development of novel bacterial mechanisms of resistance. While only a fraction of these efforts will ultimately result in new drug approvals, it is safe to say that we are on the verge of developing some potentially lifesaving medications. For the first time in a long time, a glimmer of hope is evident in the horizon.
- O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=2ahUKEwiaqMKsx43mAhWAxcQBHYofDyoQFjABegQIBhAC&url=https%3A%2F%2Famr-review.org%2Fsites%2Fdefault%2Ffiles%2F160518_Final%2520paper_with%2520cover.pdf&usg=AOvVaw0kDaiLbLr8dtJAJDnpiBEF. Accessed November 28, 2019.
- Taylor J, Hafner M, Yerushalmi E, et al. Estimating the economic costs of antimicrobial resistance: model and results. https://www.rand.org/pubs/research_reports/RR911.html. Accessed November 28, 2019.
- Imai Y, Meyer KJ, Iinishi A, Favre-Godal Q, Green R, Manuse S, Caboni M, Mori M, Niles S, Ghiglieri M, Honrao C, Ma X, Guo J, Makriyannis A, Linares-Otoya L, Böhringer N, Wuisan ZG, Kaur H, Wu R, Mateus A, Typas A, Savitski MM, Espinoza JL, O’Rourke A, Nelson KE, Hiller S, Noinaj N, Schäberle TF, D’Onofrio A, Lewis K. A new antibiotic selectively kills Gram-negative pathogens. Nature. 2019 Nov 20. doi: 10.1038/s41586-019-1791-1. [Epub ahead of print] PubMed PMID: 31747680.
- Qiu Y, Chan ST, Lin L, Shek TL, Tsang TF, Zhang Y, Ip M, Chan PK, Blanchard N, Hanquet G, Zuo Z, Yang X, Ma C. Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins. Bioorg Chem. 2019 Nov;92:103203. doi: 10.1016/j.bioorg.2019.103203. Epub 2019 Aug 16. PubMed PMID: 31446238.
- Nicolas I, Bordeau V, Bondon A, Baudy-Floc’h M, Felden B. Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance. PLoS Biol. 2019 Jul 9;17(7):e3000337. doi: 10.1371/journal.pbio.3000337. eCollection 2019 Jul. PubMed PMID: 31287812; PubMed Central PMCID: PMC6615598.
- Varela-Ortiz DF, Barboza-Corona JE, González-Marrero J, León-Galván MF, Valencia-Posadas M, Lechuga-Arana AA, Sánchez-Felipe CG, Ledezma-García F, Gutiérrez-Chávez AJ. Antibiotic susceptibility of Staphylococcus aureusisolated from subclinical bovine mastitis cases and in vitro efficacy of bacteriophage. Vet Res Commun. 2018 Sep;42(3):243-250. doi: 10.1007/s11259-018-9730-4. Epub 2018 Jul 24. PubMed PMID: 30043292.
- Seo BJ, Song ET, Lee K, Kim JW, Jeong CG, Moon SH, Son JS, Kang SH, Cho HS, Jung BY, Kim WI. Evaluation of the broad-spectrum lytic capability of bacteriophage cocktails against various Salmonella serovars and their effects on weaned pigs infected with Salmonella Typhimurium. J Vet Med Sci. 2018 Jun 6;80(6):851-860. doi: 10.1292/jvms.17-0501. Epub 2018 Apr 4. PubMed PMID: 29618667; PubMed Central PMCID: PMC6021886.
- Leitner L, Sybesma W, Chanishvili N, Goderdzishvili M, Chkhotua A, Ujmajuridze A, Schneider MP, Sartori A, Mehnert U, Bachmann LM, Kessler TM. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 2017 Sep 26;17(1):90. doi: 10.1186/s12894-017-0283-6. PubMed PMID: 28950849; PubMed Central PMCID: PMC5615798.
- https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development. Accessed November 28, 2019.